Tgfβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration
Tgfβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration
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DOI：
10.7554/elife.51779
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发表时间：
2020-06-05
期刊：
影响因子：
7.7
通讯作者：
Huang, Alice H.
中科院分区：
文献类型：
--
作者：
Kaji, Deepak A.;Howell, Kristen L.;Huang, Alice H.
肌腱损伤很常见，且愈合潜力较差。肌腱损伤治疗方法的缺乏是由于我们对驱动肌腱再生的细胞和分子途径的了解有限。使用新生儿肌腱再生的小鼠模型，我们确定 TGF β 信号传导是驱动新生儿肌腱再生的主要分子途径。通过靶向基因删除、小分子抑制和谱系追踪，我们阐明了肌腱再生的 TGF β 依赖性和 TGF β 独立机制。重要的是，功能恢复取决于经典的 TGF β 信号传导，而功能丧失是由于 Scleraxis 谱系和非 Scleraxis 谱系来源的肌腱细胞募集受损所致。我们表明，新生肌腱细胞的募集直接需要 TGF β 信号传导，并且 TGF β 配体在肌腱中受到正向调节。总的来说，这些结果显示了经典 TGF β 信号在肌腱再生中的功能作用，并为区分再生与纤维化愈合的不同细胞活动提供了新的见解。
Tendon injuries are common with poor healing potential. The paucity of therapies for tendon injuries is due to our limited understanding of the cells and molecular pathways that drive tendon regeneration. Using a mouse model of neonatal tendon regeneration, we identified TGF beta signaling as a major molecular pathway that drives neonatal tendon regeneration. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGF beta-dependent and TGF beta-independent mechanisms underlying tendon regeneration. Importantly, functional recovery depended on canonical TGF beta signaling and loss of function is due to impaired tenogenic cell recruitment from both Scleraxis-lineage and non-Scleraxis-lineage sources. We show that TGF beta signaling is directly required in neonatal tenocytes for recruitment and that TGF beta ligand is positively regulated in tendons. Collectively, these results show a functional role for canonical TGF beta signaling in tendon regeneration and offer new insights toward the divergent cellular activities that distinguish regenerative vs fibrotic healing.